Untreated non-Hodgkin Lymphoma Research Articles

A Multicenter, Prospective Clinical Study of the R-CDOP Regimen in Previously Untreated Non-Hodgkin Lymphoma with High Tumor Burden

Background: The treatment of non-Hodgkin lymphoma (NHL) with high tumor burden is facing severe challenges. The response rate and survival of R-CHOP treatment still need to be further explored in these patients. Pegylated liposomal doxorubicin (PLD) is a promising alternative drug to the current regimen, with a safety and efficacy profile through the enhanced permeability and retention effect and longer circulation1-3, and especially less cardiotoxic compared with traditional anthracyclines4. We conducted this prospective study to evaluate the efficacy and safety of PLD combined with R-COP (R-CDOP) regimen in treatment for previously untreated (TN) NHL with high tumor burden. Methods: This study was a single-arm, multicenter, prospective clinical trial (NCT05040555). TN Patients with CD20+ diffuse large B-cell lymphoma or grade 3b follicular lymphoma with high tumor burden were recruited. Patients are considered to have high tumor burden if they meet at least one of the following criteria: (1) presence of at least three lymph nodes with a diameter of 3 cm or more; (2) presence of any lymph nodes or extranodal masses with a diameter of 7 cm or more; (3) presence of hepatomegaly and splenomegaly confirmed by PET-CT; Spleen: female > 15cm, male > 16cm); (4) presence of pleural and peritoneal effusions determined through cytological examination, flow cytometry, or diagnosed by PET-CT, (5) LDH levels exceeding 3 times the upper limit of normal value, and (6) PET-CT TMTV exceeding 220cm3. The patients received PLD (30-35mg/ m2, d1) plus Rituximab (375mg/m2, d0), Cyclophosphamide (750mg/ m2, d1), Vindesine (3mg/ m2, d1) / Vincristine (1.4mg/m2, d1) and Prednisone (60mg/ m2, d1-5) Q3W for 4 (Limited-stage lymphoma) or 6 (Advanced lymphoma) cycles with an additional 2 cycles of Rituximab therapy. The primary endpoints was objective response rate (ORR). The secondary endpoint were complete response rate (CRR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: At the data cut-off of 5 June 2023, 44 eligible pts were enrolled (Table 1). The ORR and CRR was 84.2% (32/38) [95%CI, 68.8%-94.0%] and 60.5% (23/38) [95%CI, 43.4-76.0%], respectively. The DCR was 89.5% (34/38) [95%CI, 75.2%-97.1%]. The median PFS was 14.4 months [95%CI, 4.7%-24.2%], and the median OS was not reached. The median PFS and OS will be updated after long-term follow-up. The most common grade 3/4 AEs were neutropenia (29.5%), leucopenia (25.0%) and anemia (11.4%). Left ventricular ejection fraction (LVEF) declined in 1(1/44, 2.3%) pt, but did not fall below 50%. Congestive heart failure was not occurred. Dose adjustment and treatment delay due to AE occurred in only one pt, and no treatment termination due to AE occurred except for 1 patient death. Conclusions: The preliminary results of the study indicate that the R-CDOP regimen is safe and shows promising efficacy for treating TN NHL with a high tumor burden. References： 1. Hashizume H, Baluk P, Morikawa S, et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol. 2000;156 (4):1363-1380 2. Gabizon A, Shmeeda H, Grenader T. Pharmacological basis of pegylated liposomal doxorubicin: impact on cancer therapy. Eur J Pharm Sci. 2012;45(4):388-398. 3. Sadzuka Y, Sugiyama I, Tsuruda T, et al. Characterization and cytotoxicity of mixed polyethyleneglycol modified liposomes containing doxorubicin. Int J Pharm. 2006;312(1-2):83-89. 4. Lu B, Shen L, Ma Y, et al. Cardiovascular adverse events associated with cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone with or without rituximab ((R)-CDOP) in non-Hodgkin's lymphoma: A systematic review and meta-analysis. Front Pharmacol. 2022;13:1060668.

Longitudinal assessment of quality of life in indolent non-Hodgkin lymphomas managed with active surveillance

There are limited data describing the impact of active surveillance on longitudinal health-related quality of life (HRQoL) in patients with indolent non-Hodgkin lymphomas (NHL). A cohort of untreated indolent NHL patients completed FACT-LYM questionnaires at 6, 12, 18, 24, and 36 months after diagnosis. Longitudinal FACT-LYM scores were analyzed by ANOVA and generalized linear mixed models. Indolent NHL scores were compared to norm general population scores. A total of 52 patients were identified, of which 46 (88%) remained on active surveillance at 36 months. There was no significant change in any of the FACT-LYM scores over 36 months. As compared to the general population, indolent NHL patients had higher, clinically meaningful scores in physical, functional, and social well-being, but not emotional well-being. Patients with indolent NHL on active surveillance have globally preserved HRQoL for up to 3 years after diagnosis. Emotional well-being continues to be an unmet need during active surveillance.

Using nucleosome levels, copy number alterations, and DNA methylation to profile disease state through liquid biopsy.

e15014 Background: Nucleosomes are the repeating unit of chromatin that contain important signals for proper genomic function and transcriptional activity. Upon cell death, chromatin is fragmented, and nucleosomes are released into circulation and thus, detectable in liquid biopsy. Cell death naturally occurs over time and increases in a variety of diseases resulting in elevated levels of circulating nucleosomes and the genetic and epigenetic signatures they carry. These signatures contain important information about the cells from which they were derived, as well as the reason for them being in circulation. Methods: We measured circulating nucleosome levels, using Volition’s Nu.Q H3.1 sandwich ELISA across a healthy cohort spanning 40-85 years of age as well as patients whom had been diagnosed with Non-Hodgkin's Lymphoma (NHL), some of which were untreated and others that had undergone treatment. Additionally, to demonstrate that the correlation between nucleosome (Nu.Q) levels and copy number alterations is specific to cancer, we assessed the genomic integrity of an NHL sample with a Nu.Q level of 744 ng/ml and a sepsis sample with Nu.Q level of 3,281 ng/ml using low coverage Oxford Nanopore whole genome sequencing to identify genomic amplifications and deletions. We further used cell type specific methylation patterns to identify the cell of origin of cfDNA in each sample. Results: Importantly, we found no significant correlation between nucleosome level and age in our healthy cohort (R2= 0.0004; 40-49: N = 10, mean = 39 ng/ml; 50-59: N = 10, mean = 18 ng/ml; 60-69: N = 10, mean = 35 ng/ml; 70-79: N = 15, mean = 34 ng/ml; 80-85: N = 5, mean = 32 ng/ml). We did however find elevated nucleosome levels in untreated NHL patients (N = 4, mean 646 ng/ml) and that nucleosome levels in NHL patients that had undergone treatment were reduced (N = 29, mean = 180 ng/ml). Using copy number changes, we found that the fraction of cfDNA estimated to be derived from the tumor in the NHL sample was 54% and were able to detect amplifications in chromosomes 10, 11 and 18 and deletions in chromosomes 1, 8, 17, 18 and 23, whereas we found no copy number alterations present in the cfDNA sample derived from a sepsis patient and a tumor fraction of 0. Furthermore, using cell type specific methylation patterns to deconvolute the data we found that a large fraction of the cfDNA in the NHL sample was derived from B-cells consistent with the NHL sample being of B-cell origin whereas we determined that the cell of origin of the cfDNA in the sepsis sample was Neutrophils. Conclusions: This data shows that nucleosome levels, as measured by Nu.Q, can be used in conjunction with shallow sequencing and DNA methylation profiles to define tumor fraction and cell of origin in liquid biopsy.

A multicenter, phase II study of full-dose THP-COP therapy for elderly patients with newly diagnosed, advanced-stage, aggressive non-Hodgkin lymphoma

The cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen, containing doxorubicin (DXR), which is a key drug for aggressive non-Hodgkin lymphoma (NHL), is a standard chemotherapeutic regimen; however, its administration in elderly patients is often intolerable. Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracycline developed in Japan. We have conducted a phase II trial of a full-dose THP-COP (modified CHOP regimen with DXR replaced by THP) regimen for elderly patients with newly diagnosed, advanced-stage, aggressive NHL. Patients aged 70-79 years old with previously untreated NHL according to the Working Formulation (D through H and J), disease stage I with a bulky mass or stage II-IV, and performance status of 0-1 were eligible. The THP-COP regimen, which consisted of 750-mg/m2 cyclophosphamide, 50-mg/m2 THP, 1.4-mg/m2 vincristine (capped at 2.0 mg) on day 1, and 100-mg prednisolone daily on days 1 to 5, was delivered every 3 weeks for 6 cycles. The primary endpoint was complete response (CR) rate. Twenty-nine patients were enrolled in the study. The CR rate was 65.5% (95% confidence interval, 45.7-82.1%). The 3-year failure-free and overall survival rates were 54.1% and 53.9%, respectively. The most frequent observed grade 3 or 4 toxicity was neutropenia, which occurred in 80% of the patients. Grade 3 cardiac dysfunction was observed in one patient. The full-dose THP-COP regimen exhibited similar efficacy and safety, and a tendency for less cardiac toxicity, when compared with the standard CHOP regimen in elderly Japanese patients with newly diagnosed, advanced-stage, aggressive NHL.

The Efficacy of PET-CT in Detecting Bone Marrow Involvement in Patients with Newly Diagnosed Lymphoma: A Retrospective Study

Background: Patients diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) undergo various investigations to determine disease stage. This includes Positron Emission Tomography with Computed Tomography (PET-CT) scan and bone marrow biopsy (BMB), which has historically been considered the gold standard for detecting involvement of the bone marrow (BM) by lymphoma. Recent studies have suggested that PET-CT scans can detect BM involvement in most patients with lymphoma. As such, there is growing interest into whether or not PET-CT scans may replace the need for BMB in staging patients with lymphoma.Objective: We conducted a retrospective chart review of patients newly diagnosed with lymphoma at our local cancer centre to evaluate the diagnostic performance of PET-CT scans in detecting BM involvement.Methods: Patients were eligible for inclusion if they were age 18 or older, had previously untreated HL or NHL diagnosed from January 2012 to August 2016, and underwent both BMB and PET-CT scan at time of staging. We collected the results of BM aspirate, flow cytometry, cytogenetics and biopsy. Patients were considered to have BM involvement if they had a positive BMB. PET-CT scans were retrospectively re-analyzed by two readers from the Division of Nuclear Medicine. Both were blinded to the patients' clinical information, including lymphoma diagnosis and BMB results. BM positivity by PET-CT scan was characterized as being either diffuse (relatively uniform increase in tracer uptake in the BM) or focal (localized increase in tracer uptake to one or more demarcated regions of BM). We performed sensitivity and specificity analyses of PET-CT scans.Results: The study included 110 patients: 102 patients with NHL and 8 with HL. The most common NHL subtype was diffuse large B-cell lymphoma (DLBCL) (n=40). For the entire cohort of patients with NHL, the sensitivity and specificity of PET-CT scan for diagnosing BM involvement were 78% (95% CI: 52-93%) and 86% (95% CI: 76-92%), respectively (Table 1). For patients with DLBCL, the sensitivity and specificity of PET-CT scan were 100% (95% CI: 52-100%) and 79% (95% CI: 63-91%), respectively. In this group, none of the patients with a negative PET-CT scan had a positive BMB. Five of the 7 patients with positive PET-CT scans but negative BMB had focal BM involvement on PET-CT scan.Conclusions: Although limited by small sample size, our data suggests that PET-CT scan is particularly adept at detecting BM involvement in patients with DLBCL and may detect focal BM involvement missed by BMB. The high sensitivity of PET-CT scan may lend support to clinicians foregoing BMB in patients with newly diagnosed lymphoma if imaging with PET-CT scan does not show involvement of the BM by lymphoma. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ovarian dlbcl presenting as a very large ovarian mass in a young woman – a case report (and potential frozen section pitfall)

While ovarian involvement as a late manifestation of disseminated non-Hodgkin lymphoma (NHL) is not uncommon, primary ovarian NHL, or NHL presenting for the first time as an ovarian mass, is rare, having a reported incidence of around 0.5% of all untreated NHL and 1.5% of untreated ovarian neoplasms. This case study reports a 27-year-old woman who underwent a unilateral salpingo-ophorectomy and staging for a very large, rapidly enlarging, right ovarian mass, suspected clinically of being a dysgerminoma. On frozen section, the tumour was favoured to be a germ cell tumour, with juvenile granulosa cell tumour also not excluded. On permanent section, however, the tumour more clearly demonstrated morphological features and immunological features in keeping with a large B-cell non-Hodgkin lymphoma. Coupled with FISH analysis showing no evidence of a MYC gene rearrangement, a diagnosis of DLBCL, NOS, double expressor phenotype, was ultimately made. This case serves as a reminder that, although rare as an initial presentation in the ovary, lymphoma should be considered by pathologists in the differential diagnosis of ovarian tumours, including at frozen section, where consideration should also be given to obtaining fresh tissue for flow cytometry. 1.Dimopoulos MA, Daliani D, Pugh W, et al. Primary ovarian non-Hodgkin's lymphoma: outcome after treatment with combination chemotherapy. Gynecol Oncol 1997; 64: 446–50.

Elderly Aggressive-Histology Non-Hodgkin's Lymphoma: First-Line VNCOP-B Regimen Experience on 350 Patients

Age is a risk factor and a prognostic parameter in elderly aggressive-histology non-Hodgkin's lymphoma (NHL) patients. Several adapted chemotherapeutic regimens have recently been designed and tested on elderly patients. Several of these trials have shown that older aggressive-histology NHL patients can benefit from specific and adequate treatment capable of curing a percentage of these patients. Between January 1992 and September 1997, 350 previously untreated aggressive-histology NHL patients greater than 60 years of age were treated with a combination therapy including cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (VNCOP-B). Complete remission (CR) was achieved by 202 (58%) patients and partial remission (PR) by 87 (25%), whereas the remaining 61 (17%) patients were nonresponders. The overall response rate (CR + PR) was 83%. Clinical and hematologic toxicities were modest, because 71% of the patients received granulocyte colony-stimulating factor (G-CSF). The CR rates for the three age groups (60 to 69, 70 to 79, and >/=80 years) were similar: 61%, 59%, and 56%, respectively. At 5 years, the relapse-free survival rate was 65%, the overall survival rate was 49%, and the failure-free survival rate was 33%. In the multivariate analysis, prognostic factors associated with longer survival or longer relapse-free survival turned out to be localized disease stage (P =.001) and good performance status (P =.0002). Application of the International Prognostic Factor Index was significantly associated with outcome (P =.001). These data confirm on a large cohort of patients that the VNCOP-B regimen is effective in inducing good CR and relapse-free survival rates with only moderate toxic effects in elderly aggressive-histology NHL.

The miRNA Profile in Non-Hodgkin's Lymphoma Patients with Secondary Myelodysplasia.

Myelodysplastic syndromes are a group of clonal diseases of hematopoietic stem cells and are characterized by multilineage dysplasia, ineffective hematopoiesis, peripheral blood cytopenias, genetic instability and a risk of transformation to acute myeloid leukemia. Some patients with non-Hodgkin lymphomas (NHLs) may have developed secondary myelodysplasia before therapy. Bone marrow (BM) hematopoiesis is regulated by a spectrum of epigenetic factors, among which microRNAs (miRNAs) are special. The aim of this work is to profile miRNA expression in BM cells in untreated NHL patients with secondary myelodysplasia. A comparative analysis of miRNA expression levels between the NHL and non-cancer blood disorders samples revealed that let-7a-5p was upregulated, and miR-26a-5p, miR-199b-5p, miR-145-5p and miR-150-5p were downregulated in NHL with myelodysplasia (p < 0.05). We for the first time developed a profile of miRNA expression in BM samples in untreated NHL patients with secondary myelodysplasia. It can be assumed that the differential diagnosis for blood cancers and secondary BM conditions based on miRNA expression profiles will improve the accuracy and relevance of the early diagnosis of cancerous and precancerous lesions in BM.

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Ongoing Study of Obinutuzumab Short Duration Infusion in Patients with Previously Untreated Advanced Follicular Lymphoma

Introduction: In the Phase III GALLIUM study (NCT01332968), obinutuzumab (G) in combination with chemotherapy (G-chemo) demonstrated improved progression-free survival (PFS) and a comparable tolerability profile to rituximab (R)-chemo, in patients with previously untreated follicular lymphoma (FL) (Marcus et al. N Engl J Med 2017). In addition to developing more efficacious treatments for FL, there is also a need for more convenient treatments. The administration of G is associated with infusion-related reactions (IRRs). The incidence of IRRs is greatest with the first infusion and decreases significantly with subsequent infusions (Marcus et al. N Engl J Med 2017). To reduce this risk, an IRR risk-reduction strategy is used in clinical practice. However, this means that administration of G can take approximately 4 hours. Shorter infusion times would yield substantial time savings for patients and benefit outpatient infusion facilities by increasing the number of infusion chairs available during clinic hours and improving nursing efficiency. Previous studies with R have led to the development of a 90-minute short duration infusion (SDi), which is now widely used if the first dose of R is well tolerated. Two Phase II studies have previously evaluated the safety and efficacy of a 90-minute SDi of G. The GATHER study (NCT01414855), in patients with previously untreated advanced diffuse large B-cell lymphoma (Sharman et al. Leuk Lymphoma 2018) and the GATS study in Japanese patients with previously untreated non-Hodgkin lymphoma (Ohmachi et al. Jpn J Clin Oncol 2018) both demonstrated that G can be safely administered as a 90-minute SDi, after the initial cycle (C). Here, we report details of the ongoing GAZELLE study (NCT03817853; MO40597), an open-label, multicenter, Phase IV study investigating the safety of G-chemo, with G administered as a SDi (approximately 90 minutes) from C2 onwards in patients with previously untreated advanced FL, who have received G-chemo at the standard infusion rate without experiencing a grade (Gr) 3 or 4 IRR during C1. Methods: Patients with CD20-positive, previously untreated stage III or IV FL, or stage II bulky disease (Groupe d'Etude des Lymphomes Folliculaires [GELF] criteria for initiating treatment, Eastern Cooperative Oncology Group performance status [ECOG PS] 0−2, life expectancy ≥12 months) will receive G (1000mg) intravenously on Day (D) 1, D8, and D15 of C1, and on D1 of subsequent cycles (Figure), in combination with chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP], cyclophosphamide, vincristine, and prednisone [CVP], or bendamustine at the discretion of the investigator site). The standard infusion rate of G will be administered in C1 (obinutuzumab [Gazyva] prescribing information, 2017). The primary endpoint is incidence of Gr ≥3 IRRs during C2 in patients who had previously received G at the standard infusion rate during C1, without experiencing a Gr ≥3 IRR. For the purposes of the study, an IRR was defined as an adverse event (AE) occurring during or ≤24 hours from the end of G infusion and judged by the investigator as related to the infusion. The rate of G administration at subsequent cycles will be adjusted according to the occurrence and severity of IRRs. Only patients who do not experience a Gr ≥3 IRR during C1 will receive the faster SDi infusion from C2 onwards. If any Gr ≥3 IRR occurs during or after C1 then the next dose of G will be administered at the standard infusion rate. The investigator will decide if the patient can restart with the SDi. Secondary safety endpoints include AEs, time to IRRs, type and duration of Gr ≥3 IRRs and duration of G administration by cycle. Secondary efficacy endpoints include investigator-assessed overall response rate at end of induction, PFS and overall survival at the end of the study, and complete response rate at 30 months. Total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 4 years. It is estimated that 112 patients will be enrolled. Disclosures Canales: Novartis: Honoraria; SOBI: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; iQone: Honoraria; Sandoz: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau. Buchholz:Scripps Health Care System: Employment; Scientific Advisory Committee, Roche/Genetech for the Study of the Abstract: Membership on an entity's Board of Directors or advisory committees. Mason:Abivax: Consultancy. Parreira:F.Hoffmann-La Roche Ltd: Employment, Equity Ownership, Honoraria. Tomiczek:F. Hoffmann-La Roche Ltd: Employment. Hübel:Sanofi: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, expenses , Speakers Bureau; Hexal: Consultancy; Roche: Consultancy, Other: Travel, Accommodations, expenses , Research Funding, Speakers Bureau; Servier: Consultancy, Research Funding, Speakers Bureau.

SUN-326 Hypoglycemia and Lactic Acidosis: The Deadly Signs of Untreated Non-Hodgkin's Lymphoma

Introduction The presentation of hypoglycemia with lactic acidosis is rare, though well-described. It is most commonly associated with hematologic malignancies and is attributed to the Warburg effect in which cells consume large amounts of glucose through the glycolytic pathway with lactic acid production, even in aerobic conditions. Clinical Case 64yo WM with cirrhosis due to hemochromatosis, atrial fibrillation, type 2 diabetes mellitus managed by diet, initially presented with weakness, malaise and thrombocytopenia. Imaging revealed splenomegaly, bilateral adrenal masses, and diffuse lymphadenopathy. He was admitted, given IV fluid hydration, and discharged to have outpatient lymph node biopsy. Prior to biopsy he developed worsening weakness, fatigue, shortness of breath, and hypoxia. Lactate was 8.1mmol/L, n=0.7-2.1. He was admitted for sepsis secondary to pneumonia. During hospitalization, he was noted to be hypoglycemic (serum glucose 40mg/dL), requiring continuous dextrose infusion and dextrose 50% boluses. Evaluation was consistent with insulin independent hypoglycemia with labs as follows: Insulin <1 microU/mL (2-25), c-peptide 0.65ng/mL (0.78-5.19), proinsulin 4.2pmol/L (3.6-22), beta-hydroxybutyrate 4.07mg/dL (0.2-2.8), glucose 49mg/dL then 44mg/dL 30 minutes after administration of glucagon. ACTH 8.1pg/mL (7.2-63) and cortisol 11mcg/dL then 14.8mcg/dL after cosyntropin stimulation. He was started on stress dose steroids. Lactic acidosis persisted and worsened (>15mmol/L). Repeat CT imaging was obtained to search for potential source of lactic acidosis, though none was found. It was later noted that increasing lactate levels occurred with increased dextrose administration. A perirenal lymph node biopsy was performed. Shortly after the procedure, the patient rapidly decompensated. He was started on continuous renal replacement therapy and given rasburicase for suspected tumor lysis syndrome. Despite these efforts, the patient died. Pathology later returned positive for Non-Hodgkin’s Lymphoma. Discussion In this case, hypoglycemia was initially confounded by a history of cirrhosis and possible adrenal insufficiency. However, no improvement with steroids and worsening of lactic acidosis with increasing dextrose administration demonstrated that hypoglycemia was due to the Warburg effect in the setting of undiagnosed Non-Hodgkin’s Lymphoma. Recognizing this phenomenon is imperative as it coincides with high mortality, and the treatment of underlying disease may be the only effective option. References Georges C. Elhomsy, et al; “Hyper-Warburgism,” a Cause of Asymptomatic Hypoglycemia with Lactic Acidosis in a Patient with Non-Hodgkin's Lymphoma, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 12, 1 December 2012, Pages 4311-4316.

ASCO 2017 Meeting Summary: Updates to Practice-Changing Studies in Untreated Non-Hodgkin Lymphoma

The 2017 annual meeting of the American Society of Clinical Oncology took place in Chicago, Illinois, 2–6 June. At the meeting, results from key studies in the first-line treatment of indolent non-Hodgkin lymphoma (iNHL) were presented. Of those studies, two were selected for oral presentations: 9-year follow-up data from the STiL NHL1 trial, which compared the efficacy and safety of bendamustine plus rituximab (BR) with those of rituximab plus cyclophosphamide–vincristine–prednisone–doxorubicin (R-CHOP); and 5-year follow-up data from the bright study, which compared BR with R-CHOP and R-CVP (rituximab plus cyclophosphamide–vincristine–prednisone) combined. Our meeting report describes the foregoing studies and includes interviews with key investigators, plus commentaries from three Quebec hematologists on the potential effects for Canadian practice.

Safety and Tolerability of Obinutuzumab (GA101) with Shorter Duration of Infusion in Japanese Patients with Previously Untreated CD20-Positive B-Cell Non-Hodgkin's Lymphoma (NHL)-Comparison with GAO4915g (GATHER) and BO21005 (GOYA) Studies

BackgroundObinutuzumab (GA101) is a novel humanized, glycoengineered Type II anti-CD20 monoclonal antibody. It has greater direct cell death induction and antibody-dependent cell-mediated cytotoxicity and lower complement-dependent cytotoxicity than Type I anti-CD20 antibody rituximab. Studies of obinutuzumab in patients (pts) with previously untreated or relapsed/refractory NHL demonstrated clinical activity with an acceptable safety profile. Infusion-related reactions (IRRs) were the most common adverse event, typically associated with the first infusion. Obinutuzumab 1000 mg is being administered over 4 hrs 15 min for the first infusion on Cycle 1 Day 1, and over 3 hrs 15 min for subsequent infusions. Shortening administration times can result in greater patient convenience and more efficient use of infusion facilities. To evaluate the tolerability of a Shorter Duration of Infusion (SDI), we conducted a Phase II study (JO29737, JapicCTI-152848, 'GATS') of G-CHOP (obinutuzumab in combination with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone]) in Japanese pts with previously untreated CD20-positive B-cell NHL.MethodsThis study included adult pts with previously untreated CD20-positive B-cell NHL. Treatment consisted of 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, with additional doses on Days 8 and 15 of Cycle 1) plus standard CHOP on Day 1 of Cycles 1-6. Obinutuzumab SDI is administered over 1 hr 30 min. Obinutuzumab was administered as an SDI from Cycle 2 to pts who met the following criteria: (1) No ≥ Gr 3 IRR related to obinutuzumab during regular infusions (RI) in Cycle 1, and (2) Lymphocyte count ≤ 5000/µL in peripheral blood prior to SDI. Primary endpoints were tolerability of SDI, pharmacokinetics (PK) of obinutuzumab. Tolerability of SDI was assessed by incidence of ≥ Gr 3 IRR in Cycle 2. Secondary endpoints were overall safety profile and efficacy. IRRs were defined as AEs related to obinutuzumab occurring during infusion or within 24 hrs from the end of infusion. Results were compared to the multicenter, open-label, randomized GOYA study (phase III, RI G-CHOP), and the multicenter, open-label, single-arm GATHER study (phase II, SDI G-CHOP). The GOYA study included 111 Japanese pts.ResultsAt database lock date, 35 pts were enrolled and treated, including 19 diffuse large B-cell lymphoma, 13 follicular lymphoma, and 3 other histologies; median age was 66 yrs (range, 35-78); 12/35 female; Ann Arbor stage I 11.4%, II 25.7%, III 20.0%, IV 42.9%; 7/35 positive bone marrow involvement. In 7 pts, treatment was prematurely discontinued due to AE (n=3; infected dermal cyst, bronchiolitis, and pneumonia aspiration, 1 pt each), progressive disease (n=2), or physician’s decision (n=2). Thirty-three pts received at least one SDI of obinutuzumab, given in Cycle 2 and subsequent cycles in 31 pts. Overall, 48.6% of pts (17/35) experienced IRRs. They were Gr 1/2 in all cases and occurred most commonly on Day 1 Cycle 1 (RI). No SDI-associated IRR was observed in Cycle 2, and very rare cases (2 pts) were noted in Cycles 6, 7, and 8. IRRs occurring in ≥5% pts were pyrexia (25.7%), chills (8.6%), and nausea, blood pressure increased, and headache (5.7%). Gr ≥3 AEs observed in ≥10% of pts were neutropenia (40.0%), neutrophil count decreased (25.7%), febrile neutropenia (17.1%), and leukopenia (14.3%). Obinutuzumab concentration just after Cycle 2 SDI was the same level as the concentration in Cycle 8. This shows PK reached a steady state at Cycle 2 and was not affected by shortening of administration. From PK analysis in the GATS study, AUC7day was 4170±885 µg·day/mL and t1/2 was 15.4±7.0 day, similar to the GATHER values (AUC7day, 3300±1130 µg·day/mL; t1/2, 23.0±15.9 day) after considering individual variability. No ethnic difference was observed. Overall response rate was 82.9% (29/35) (CR 62.9% [22/35], PR 20.0% [7/35]); 2 pts were not evaluable for response.ConclusionsObinutuzumab can be safely administered as SDI. No SDI-associated IRR was observed in Cycle 2. A few IRRs were observed with SDI in later cycles, but all were tolerable and manageable. RI and SDI have comparable safety, PK, and efficacy profiles in Japanese and non-Japanese. DisclosuresHatake:Meiji-Seika: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Otsuka: Consultancy; Chugai: Research Funding. Izutsu:Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding. Kinoshita:Janssen: Honoraria; Solasia: Research Funding; Eisai: Honoraria, Research Funding; Ono: Research Funding; Gilead: Research Funding; Kyowa Kirin: Honoraria; Zenyaku: Honoraria, Research Funding; Takeda: Research Funding; Chugai: Honoraria, Research Funding. Tobinai:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; HUYA Bioscience: Honoraria; Chugai Pharma: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Zenyaku Kogyo: Honoraria; SERVIER: Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma KK: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.

Risk Factors for Early Mortality in Fragile Patients with Non-Hodgkin Lymphoma at Diagnosis Who Need Hospitalization in a Developing Country

BackgroundNot infrequently, doctors face a major challenge concerning how to choose the best treatment for fragile patients with cancer, especially for those who need inpatient care. Usually these patients present exclusion criteria to be treated in a curative intention at diagnosis with performance status > 2. In the other hand these patients are not included in clinical trials. In our institution it is not uncommon to receive patients with poor performance status.ObjectiveWith the aim to individualize the best approach for fragile adults with non-Hodgkin lymphoma (NHL) at diagnosis, we conducted a retrospective study that could identify risk factors for early mortality who needed inpatient care.MethodologyEarly death was considered up to 120 days after the biopsy date. Inclusion criteria were untreated NHL patient ≥ 18 years with indication to start a curative treatment. Exclusion criteria were patient with intention to palliative care, salvage therapy, diagnosis investigation and late death after 120 days. All patients were analyzed for clinical features and laboratory data.ResultsWe hospitalized 204 patients with NHL at diagnosis from January 2014 to January 2015 in our cancer center. Sixty four patients (31.3%) met the eligibility criteria. The median age was 56 (20-80 years) years and 39 (60.9%) were male. The subtype of diffuse large B cell lymphoma represented 37 (57.8%) of cases. Forty seven (73.4%) patients had Ann Arbor Stage III or IV, twenty six (40.6%) presented with Performance Status > 2, fifty (78.1%) had elevated serum LDH, forty seven (73.4%) had extranodal involvement and forty three (67.2%) had an International Prognostic Index > 2. Twenty six (40.6%) patients had serum albumin < 3g/dL, twenty one (32.8%) were admitted at the hospital by emergency serve or intensive care unit and twenty three (35.9%) had a time of hospitalization > 20 days. The early mortality was seen in 16 (25%) patients and only two of them occurred before the chemotherapy.The multivariate analysis identified as significant risk factors for early mortality the albumin < 3g/dL with an odds ratio (OR) 4.84 and a confidence interval (CI) (1.43-16.41), p=0.0169; time of hospitalization > 20 days OR 4.48, CI (1.35- 14.84), p=0.0016 and patients that were admitted at hospital by emergence service or intensive care unit OR 8.36, CI (2.35-29.66), p=0.0013.ConclusionIn this study we observed high early mortality in NHL patients that needed hospitalization at diagnosis. The main risk factors were albumin < 3g/dL, time of inpatient > 20 days and the admission via emergence or intensive care unit. Therefore, we may suggest that NHL patients who need to be hospitalized and who present at least one of those findings at diagnosis should not be treated with a full dose of chemotherapy. If possible, improvement of their clinical condition should be aimed before starting curative intention treatment. DisclosuresNo relevant conflicts of interest to declare.

Zevalin(®) (ibritumomab tiuxetan): After more than a decade of treatment experience, what have we learned?

Non-Hodgkin's lymphoma (NHL) comprises a clinically and biologically heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer (NK) cells. The disease course may range from indolent to aggressive. Zevalin(®) (ibritumomab tiuxetan) is a radioactive drug product, which is the combination of a β-emitting isotope, (90)Y, linked to the anti-CD20 monoclonal antibody (mAb), rituximab. It has demonstrated therapeutic efficacy with durable responses and allows delivery of ionizing radiation directly to the tumor site, while minimizing toxicity to normal tissue. Ibritumomab tiuxetan is indicated for treatment of patients with relapsed or refractory low-grade, follicular NHL, including patients who are refractory to rituximab, and as consolidation therapy in previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy. Despite the efficacy and acceptable safety profile of ibritumomab tiuxetan, utilization has not been broadly adopted in practice due to a number of factors. This manuscript will review the literature available for ibritumomab tiuxetan, including several new trials that are currently being studied, and discuss the rationale for use of ibritumomab tiuxetan in NHL.

Interim Analysis of a Phase 2 Study of Bortezomib Plus Rituximab Maintenance Therapy in Patients with Mantle Cell Lymphoma Status Post Autologous Stem Cell Transplantation

Interim Analysis of a Phase 2 Study of Bortezomib Plus Rituximab Maintenance Therapy in Patients with Mantle Cell Lymphoma Status Post Autologous Stem Cell Transplantation

Post Transplant Outcome of a Multicenter Phase II Study of Brentuximab Vedotin As First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT

Background:Hodgkin lymphoma (HL) patients who are relapsed/refractory to induction chemotherapy are salvaged with multiagent chemotherapy such as ICE followed by autologous hematopoietic cell transplantation (AHCT). This strategy yields a 2 year EFS of ~65%. Brentuximab vedotin (BV), an antibody drug conjugate, selectively induces apoptosis of CD30+ HL. We previously reported the response rates and toxicities of a multicenter phase II trial evaluating BV as first line salvage therapy in relapsed/refractory HL prior to AHCT. We now report the transplant outcome results of BV as first line salvage therapy in relapsed/refractory HL followed by AHCT.Patients and Methods:This is a prospective, multicenter (City of Hope, Cornell Weill Medical College), phase II trial in patients with relapsed/refractory HL prior to AHCT. All patients had biopsy proven relapsed/refractory HL post induction therapy with ABVD, BEACOPP or a combination +/- consolidative XRT. Patients were treated with 1.8 mg/kg of BV intravenously every 3 weeks for a maximum of 4 cycles. Patients who do not achieve CR after BV are allowed to receive multiagent salvage chemotherapy prior to AHCT. The primary endpoint was the best response rate according to revised Cheson criteria. Secondary endpoints were toxicities, stem cell mobilizations, engraftment analysis, and 2 year PFS/OS post AHCTResults:37 patients were accrued (Table 1). The overall best response (CR+PR) rate was 69% and CR rate was 35%. 33/37 (89%) patients successfully proceeded to AHCT (1went to alloHCT, 3 could not be salvaged). Among the 13 CR patients, all proceeded to AHCT without additional chemotherapy. Among the 12 PR patients, 4 proceeded to AHCT without additional chemotherapy while 8 received additional chemotherapy (ICE/DICE/IGEV/GND). All patients with SD/PD received additional chemotherapy with exception of 1 patient who received XRT. 24/33 patients were in CR at with 8/33 in PR and 1/33 in SD at time of AHCT.All patients were primed with cyclophosphamide/G-CSF and 9 patients received plerixafor per institutional guidelines. The median time to collect was 2 days and median cells collected was 5.9 x 10^6 CD34 cells. As AHCT conditioning regimens, 22 patients received BEAM, 9 patients received CBV, and 2 patients received BEAM plus yttrium-90 labeled anti-CD25. The median time to reach ANC engraftment was 11 days and platelet engraftment was 14 days. The response rate post AHCT was 100% in all evaluable patients. Peritransplant toxicities are not evaluated on all patients but will be updated by ASH to include all 33 patients.With a median follow up of 17.6 months, the 18 month PFS is 73%, OS is 97%, and NRM is 3%. When stratified by disease status at time of AHCT, the 18 month PFS is 78% for CR and 50% for non CR patients. The 18 month OS is 89% for CR and 88% for non CR patients. When stratified by patients who received BV only vs. BV followed by combination chemotherapy, the 18 month PFS is 80% for BV only vs. 65% for BV followed by combination chemotherapy (Fig 1). The 2 year PFS and OS will be updated by ASH presentation.Conclusion:BV as first line salvage therapy results in 89% of patient successfully going to AHCT. The overall 18 month PFS of patients who underwent AHCT is 73%, which compares favorably with historical control. Patients who received BV as the only salvage therapy prior to AHCT without combination chemotherapy had an 18 month PFS of 80%, which also compares favorably with historical control. BV prior to AHCT did not negative impact stem cell collection, engraftment, 18 month NRM, PFS or OS. Given the excellent post transplant outcome, BV as first line salvage is a viable option for relapsed/refractory HL patients undergoing AHCT.Table 1CharacteristicsN (%) or Median (Range)Age34 (11-67)Institution City of Hope Weill Cornell31 (84%) 6 (16%)Stage at Diagnosis I-II III-IV19 (51%) 18 (49%)B symptoms23 (62%)Bulky Disease (> 5 cm)32 (86%)Induction Chemotherapy ABVD ABVD/BEACOPP ABVE-PC34 (92%) 2 (5%) 1 (3%)Prior XRT9 (24%)Best Response to Induction Primary Refractory Relapsed (within 7 months)24 (65%) 13 (35%) [Display omitted] DisclosuresChen:Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Off Label Use: 90-Y ibritumomab tiuxetan is a radiotherapeutic antibody targeting CD20. It is part of a regimen indicated for treating patients with relapsed/refractory, low-grade or follicular B cell non-Hodgkin lymphoma (NHL), or patients with previously untreated follicular NHL who achieved a complete or partial response to first-line chemotherapy. Martin:Genentech, Inc.: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES, Speakers Bureau; Janssen: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Gilead: Consultancy. Siddiqi:Seattle Genetics: Speakers Bureau; Kite pharma: Other: attended advisory board meeting; Pharmacyclics/Jannsen: Speakers Bureau. Nademanee:Spectrum: Research Funding; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics Inc.: Research Funding. Forman:Mustang: Research Funding; Amgen: Consultancy.

Are the high serum interleukin-6 and vascular endothelial growth factor levels useful prognostic markers in aggressive non-hodgkin lymphoma patients?

Objective:Pro-inflammatory and pro-angiogenic cytokines play an important role in the pathogenesis of lymphoma, and recent studies have shown that cytokines can be used as prognostic markers. Non-Hodgkin lymphoma (NHL) patients with high levels of serum interleukin-6 (s-IL6) and serum vascular endothelial growth factor (s-VEGF) have poor prognosis and shorter survival time. We aimed to determine pre-treatment levels of s-IL6 and s-VEGF and their relation with known prognostic markers, especially International Prognostic Index (IPI) scores, and to examine their effects on overall survival in newly diagnosed, untreated aggressive NHL patients. Materials and Methods:The study included 51 newly diagnosed NHL patients and 17 healthy controls. Blood samples were obtained to study s-IL6 and s-VEGF cytokine levels. Results:Patients with aggressive NHL diagnosis had higher s-VEGF and s-IL6 levels than the healthy population. If the s-IL6 levels of patients were above the cut-off levels, the overall survival time was shorter. There was no relation between s-VEGF and overall survival time. Conclusion:s-IL6 is an independent prognostic factor that may be included in IPI risk classification. In addition to the s-IL6 level, age, erythrocyte sedimentation rate, beta-2 microglobulin, WHO performance status, and IPI score are independent prognostic factors that are effective, especially for overall survival, in the clinical follow-up of NHL patients.

A Phase II Trial of Bortezomib Added to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Previously Untreated Indolent Non-Hodgkin’s Lymphoma

Background: Bortezomib-containing combination chemotherapy regimens are effective in non-Hodgkin’s lymphoma (NHL), although there are limited data on toxicity in the front-line setting for indolent NHL when combined with reduced-dose vincristine-containing chemotherapy. Our group (Sinha et al, Cancer 2012) reported outcomes from a phase I study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (VR-CHOP) and found a maximum tolerated dose (MTD) of bortezomib (V) of 1.6mg/m2 with vincristine capped at 1.5 mg with an overall response rate (ORR) of 100%. Herein we report the results of our phase II study of this regimen.Patients and Methods: Eligible patients had untreated indolent NHL (small lymphocytic lymphoma [SLL], marginal zone lymphoma [MZL], or follicular lymphoma [FL] grades 1-3) meeting standard criteria for treatment or with FL international prognostic index (FLIPI) ≥3. Patients received V administered at a dose of 1.6mg/m2 on days 1 and 8 as well as rituximab (R) 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (capped at 1.5mg/dose) on day 1 and prednisone 100mg on days 1-5 of a 21-day cycle. Patients received at least 6 cycles and up to 8 cycles of therapy at the discretion of the treating physician. Patients who achieved a complete response (CR) after induction were assigned to receive maintenance R 375mg/m2 every 12 weeks for 2 years while patients with a partial response (PR) or stable disease received R 375mg/m2 along with V 1.6mg/m2 (VR), both administered weekly for 4 weeks every 6 months for up to 2 years. Response was assessed by Cheson 1999 criteria, and toxicity assessed by CTCAE version 3.0. One FL patient discontinued study therapy after cycle 2 when a central pathology review revised the diagnosis to diffuse large B-cell lymphoma. This patient was not included in the efficacy analysis but is included in the safety reports. CR rate and ORR were determined at the conclusion of induction therapy, and progression-free survival (PFS) and overall survival (OS) were evaluated by the Kaplan-Meier method from the date of study entry.Results: Thirty patients received at least 1 treatment of VR-CHOP, including 16 males and 14 females. The median age was 58 (range: 31-71), and histologies included MZL (n=5), SLL (n=4), and FL (Grade 1, n=7; Grade 2, n=12; Grade 3, n=2). FLIPI score for patients with FL were 1 (n=2), 2 (n=4), 3 (n=12), and 4 (n=3). Twenty-nine were evaluable for response, including 19 patients with CR and 10 patients with PR at the conclusion of induction therapy (CR rate of 66%; ORR of 100%). For 20 evaluable patients with FL, the CR rate was 75%. Twenty-five patients proceeded with maintenance therapy, including 6 patients who received VR and 19 patients who received R alone. Three patients with PR to induction converted to CR after maintenance with VR. Four patients received no maintenance due to refusal/lost to follow-up (n=2), toxicity (n=1), and progression (n=1). Three patients with PR received only R due to neuropathy. Four patients have relapsed or progressed on therapy, including 1 patient prior to starting maintenance, 2 patients during VR maintenance, and 1 patient who achieved a PR but was receiving R maintenance. One additional patient progressed after completing R maintenance. With a median follow-up of 39 months, 3-year PFS rate is 85.8%, and the 3-year OS rate is 96.4% (Figure). Grade ≥3 peripheral neuropathy was noted in 2 patients (7%), while grade 1-2 neuropathy occurred in 17 patients (57%). Grade 3-4 hematologic toxicities included neutropenia (n=14, 47%), thrombocytopenia (n=3, 10%), anemia (n=1, 3%), and febrile neutropenia (n=1, 3%). Eight patients experienced additional grade 3 non-hematologic toxicities, including the following which occurred in more than 1 patient: vomiting (n=3, 10%), abdominal pain (n=2, 7%), fatigue (n=2, 7%), hyperglycemia (n=2, 7%), hypokalemia (n=2, 7%), and nausea (n=2, 7%).Conclusion: VR-CHOP is highly efficacious in the front-line setting for management of patients with untreated indolent NHL, and toxicities are expected and manageable. Incidence of grade 3 peripheral neuropathy is low with incorporation of a decreased dose of vincristine, and the PFS compares favorably with previously reported outcomes in FL and indolent NHL for R-CHOP, R-Bendamustine, and R-CHOP plus maintenance R. [Display omitted] DisclosuresCohen:Janssen: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Off Label Use: Bortezomib is not currently approved for follicular lymphoma, marginal zone lymphoma, or small lymphocytic lymphoma and is being evaluated in combination with a standard induction regimen.. Kaufman:Millennium: Consultancy; Janssen: Consultancy. Nastoupil:TG Therapeutics: Research Funding; Celgene: Honoraria; Genentech: Honoraria; Janssen: Research Funding. Lechowicz:Millennium: Consultancy. Lonial:Millennium, Celgene, Novartis, BMS, Onyx: Consultancy, Research Funding. Flowers:Gilead, Spectrum, Millennium, Janssen: Research Funding; Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy.

AMC075: The Combination of Vorinostat with Chemotherapy and Rituximab Is Tolerable and Feasible in HIV-Related B-Cell Non-Hodgkin’s Lymphoma with High-Risk Features

Background: Individuals infected with human immunodeficiency virus (HIV) are at an increased risk of developing highly aggressive non-Hodgkin’s lymphoma (NHL). Superior outcomes have been recently reported for rituximab (R) plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) over R-CHOP chemotherapy in patients with HIV-associated NHL, including those with high-risk features such as high International Prognostic Index (IPI) score, non-germinal center (GC) type diffuse large B-cell lymphoma (DLBCL), and high Ki-67 expression. The proportion of NHLs harboring γ-herpesviruses, such Epstein Barr virus (EBV) and human herpesvirus 8 (HHV-8), is higher in patients with HIV-AIDS, warranting the investigation of chemotherapy in combination with new drugs that target the biology of HIV-NHL.At the AIDS Malignancy Consortium (AMC), we developed AMC075, a CTEP-sponsored phase I/randomized phase II trial using the histone deacetylase (HDAC) inhibitor (HDI) vorinostat (V) in combination with R-DA-EPOCH for the treatment of high-risk HIV-NHL. Through acetylation HDIs alter chromatin and protein function, facilitating the expression of silenced cellular genes and latent viruses in neoplasms. We hypothesized that V would enhance anti-tumor chemotherapy effects in HIV-NHL, and transiently activate latent HIV and γ-herpesviruses, leading to the elimination of virally infected reservoirs under antiviral treatment.Methods:Eligibility: HIV+ subjects with untreated NHL (non-Burkitt) with CD4 count ≥50 cell/mm3. Subjects with high-risk disease (age adjusted-IPI 2-3, or Ki-67 ≥ 80%, or DLBCL-ABC subtype, or other aggressive NHL) were eligible. Phase I study: 16 subjects were enrolled between Dec-2010 and Nov-2012. Patient characteristics were as follows: Median age 48.5 years (range 27-65), 82 % males, 63 % non-Hispanic white, 19 % black, and 13% Hispanic or Latino. Baseline absolute CD4 counts were <100 and >100 cells/mm3 in 13% and 88% respectively. The median absolute CD4 count was 263 cells/mm3(range 91-754). Eight subjects had undetectable viral loads at baseline. Three were withdrawn from study after enrolment due to eligibility or compliance issues. Twelve were treated with V-R-dose-adjusted (DA)-EPOCH. The starting dose of V was 300 mg on Days 1-5 on each of six 21-day cycles and escalated to a maximum of 400 mg on a 3 + 3 design. One subject was treated with V-R-CHOP under low-risk early stage arm, which was closed due lack of accruals.Results:Phase I study: One subject completed treatment with V-R-CHOP, under low-risk arm. Twelve high-risk subjects completed treatment with V-R-DA-EPOCH. The recommended phase II dose (RPTD) was determined at 300 mg based on dose-limiting toxicities (mainly grade 4 thrombocytopenia) observed at 400 mg level. Toxicities. Hematologic and non-hematologic toxicities after cycle 1 are summarized in table below. Pharmacokinetics. In a preliminary analysis, V did not alter doxorubicin (0.018±0.023 µg/mL), etoposide (1.60±0.49 µg/mL) or vincristine (2.86±3.10 ng/mL) steady-state concentrations across dose levels. Efficacy. Twelve of 13 subjects are still alive after completion of treatment and are on active follow-up. One subject who had central nervous system (CNS) involvement at the time of enrollment relapsed after achieving a CR and died of CNS disease progression. TableToxicity (Grade ≥ 3): Cycle 1Grade 3 (n)Grade 4 (n)Thrombocytopenia13Neutropenia24Febrile neutropenia2n/aAnemia2--Intrabdominal hemorrhage (tumor)1--Dehydration1--Tooth infection1--Fatigue1--Hyperbilirubinemia1--Conclusions: We are conducting a national trial for HIV-NHL with high-risk features combining standard chemotherapy with vorinostat designed to target the biology of these tumors. Preliminary results from the phase I portion of the study show the combination treatment is tolerable with acceptable toxicities and highly efficacious. A randomized phase II study (90 subjects) of R-DA-EPOCH with and without V is currently enrolling subjects. The primary objectives are to determine the overall toxicity and efficacy of R-DA-EPOCH with and without V in subjects with high-risk HIV-NHL. Correlative studies were designed to assess the effect of R-DA-EPOCH +/- V on latent HIV-infected reservoirs, EBV and HHV-8. Complete phase I study results will be presented at the meeting. DisclosuresRamos:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding. Off Label Use: Vorinostat is being investigated in combination with chemotherapy for the treatment of HIV-associated lymphomas. Sparano:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding; Merck: Research Funding. Moore:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding. Lee:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding. Rudek:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding. Ambinder:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding. Cesarman:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding. Noy:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding. Mitsuyasu:AIDS Malignancy Consortium: grant grant number is U01 CA121947: Research Funding; Office of AIDS Research Advisory Council, NIH : Consultancy; National Cancer Institute Board of Scientific Advisors AIDS Malignancy Subcommittee : Consultancy.